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Improvement of intestinal absorption of water-soluble macromolecules by various polyamines: intestinal mucosal toxicity and absorption-enhancing mechanism of spermine.
Int J Pharm. 2008 Apr 16; 354(1-2):126-34.IJ

Abstract

The absorption-enhancing effects of three different polyamines, spermine (SPM), spermidine (SPD) and putrescine (PUT) on the intestinal absorption of water-soluble macromolecules were examined in rats. Fluorescein isothiocyanate-labeled dextrans (FDs) with different average molecular weights were chosen as models of water-soluble macromolecules and intestinal absorption of FDs with or without these polyamines was examined by an in situ closed loop method. The intestinal absorption of fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4400 (FD4) was relatively low in the absence of these polyamines. However, its absorption was improved in the presence of 5-10mM SPM and 10mM SPD in the jejunum and 10mM SPM in the colon, while 10mM PUT had almost no absorption-enhancing effect on the intestinal absorption of FD4. Overall, the enhancing effects of these polyamines were greater in the jejunal membranes than in the colonic membranes. The absorption-enhancing effect of SPM decreased as the molecular weights of FDs increased. The intestinal membrane toxicity of 10mM SPM was evaluated by measuring the amount of protein and activity of lactate dehydrogenase (LDH) released from the intestinal epithelial cells. We also observed the morphological changes of intestinal mucosa in the presence or absence of SPM. The results indicated that the amount of protein and LDH was not changed in the presence of 10mM SPM, although we observed a significant increase in these biological markers in the presence of 3% Triton X-100, as a positive control. Furthermore, we found no significant change in the intestinal membrane with 10mM SPM by the morphological observation. These findings suggested that 10mM SPM did not cause any significant membrane damage to the intestinal epithelium. To investigate the absorption-enhancing mechanism of SPM, the transepithelial electrical resistance (TEER) of the rat jejunal membranes was studied by using a diffusion chamber method. SPM decreased the TEER values in a concentration dependent manner and 10mM SPM had almost the same effect to decrease the TEER value compared with 10mM EDTA as a positive control. These findings suggest that SPM may loosen the tight junction of the epithelium, thereby increasing the intestinal absorption of drugs via a paracellular route. In summary, polyamines, especially SPM would be one of the suitable absorption enhancers with high effectiveness and low intestinal membrane toxicity.

Authors+Show Affiliations

Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18206325

Citation

Gao, Yang, et al. "Improvement of Intestinal Absorption of Water-soluble Macromolecules By Various Polyamines: Intestinal Mucosal Toxicity and Absorption-enhancing Mechanism of Spermine." International Journal of Pharmaceutics, vol. 354, no. 1-2, 2008, pp. 126-34.
Gao Y, He L, Katsumi H, et al. Improvement of intestinal absorption of water-soluble macromolecules by various polyamines: intestinal mucosal toxicity and absorption-enhancing mechanism of spermine. Int J Pharm. 2008;354(1-2):126-34.
Gao, Y., He, L., Katsumi, H., Sakane, T., Fujita, T., & Yamamoto, A. (2008). Improvement of intestinal absorption of water-soluble macromolecules by various polyamines: intestinal mucosal toxicity and absorption-enhancing mechanism of spermine. International Journal of Pharmaceutics, 354(1-2), 126-34. https://doi.org/10.1016/j.ijpharm.2007.11.061
Gao Y, et al. Improvement of Intestinal Absorption of Water-soluble Macromolecules By Various Polyamines: Intestinal Mucosal Toxicity and Absorption-enhancing Mechanism of Spermine. Int J Pharm. 2008 Apr 16;354(1-2):126-34. PubMed PMID: 18206325.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improvement of intestinal absorption of water-soluble macromolecules by various polyamines: intestinal mucosal toxicity and absorption-enhancing mechanism of spermine. AU - Gao,Yang, AU - He,Lin, AU - Katsumi,Hidemasa, AU - Sakane,Toshiyasu, AU - Fujita,Takuya, AU - Yamamoto,Akira, Y1 - 2007/12/08/ PY - 2007/08/13/received PY - 2007/11/28/revised PY - 2007/11/30/accepted PY - 2008/1/22/pubmed PY - 2008/7/3/medline PY - 2008/1/22/entrez SP - 126 EP - 34 JF - International journal of pharmaceutics JO - Int J Pharm VL - 354 IS - 1-2 N2 - The absorption-enhancing effects of three different polyamines, spermine (SPM), spermidine (SPD) and putrescine (PUT) on the intestinal absorption of water-soluble macromolecules were examined in rats. Fluorescein isothiocyanate-labeled dextrans (FDs) with different average molecular weights were chosen as models of water-soluble macromolecules and intestinal absorption of FDs with or without these polyamines was examined by an in situ closed loop method. The intestinal absorption of fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4400 (FD4) was relatively low in the absence of these polyamines. However, its absorption was improved in the presence of 5-10mM SPM and 10mM SPD in the jejunum and 10mM SPM in the colon, while 10mM PUT had almost no absorption-enhancing effect on the intestinal absorption of FD4. Overall, the enhancing effects of these polyamines were greater in the jejunal membranes than in the colonic membranes. The absorption-enhancing effect of SPM decreased as the molecular weights of FDs increased. The intestinal membrane toxicity of 10mM SPM was evaluated by measuring the amount of protein and activity of lactate dehydrogenase (LDH) released from the intestinal epithelial cells. We also observed the morphological changes of intestinal mucosa in the presence or absence of SPM. The results indicated that the amount of protein and LDH was not changed in the presence of 10mM SPM, although we observed a significant increase in these biological markers in the presence of 3% Triton X-100, as a positive control. Furthermore, we found no significant change in the intestinal membrane with 10mM SPM by the morphological observation. These findings suggested that 10mM SPM did not cause any significant membrane damage to the intestinal epithelium. To investigate the absorption-enhancing mechanism of SPM, the transepithelial electrical resistance (TEER) of the rat jejunal membranes was studied by using a diffusion chamber method. SPM decreased the TEER values in a concentration dependent manner and 10mM SPM had almost the same effect to decrease the TEER value compared with 10mM EDTA as a positive control. These findings suggest that SPM may loosen the tight junction of the epithelium, thereby increasing the intestinal absorption of drugs via a paracellular route. In summary, polyamines, especially SPM would be one of the suitable absorption enhancers with high effectiveness and low intestinal membrane toxicity. SN - 0378-5173 UR - https://www.unboundmedicine.com/medline/citation/18206325/Improvement_of_intestinal_absorption_of_water_soluble_macromolecules_by_various_polyamines:_intestinal_mucosal_toxicity_and_absorption_enhancing_mechanism_of_spermine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(07)01002-2 DB - PRIME DP - Unbound Medicine ER -